Modafinil, C15H15NO2S of formula (I), is also known as 2-(benzhydrylsulfinyl)acetamide, or 2-[(diphenylmethyl)sulfinyl]acetamide:

Modafinil is a synthetic acetamide derivative described in the French patent no. 78 05510 and in U.S. Pat. No. 4,177,290 ('290) as presenting a “neuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and of hypermotility; and by the absence of stereotypy (except in high doses) and of potentialization of the effects of apomorphine and amphetamine”. A single administration of modafinil results in increased locomotor activity in mice and increased nocturnal activity in monkeys. Duteil et al., Eur. J. Pharmacol., 1990, 180, 49. Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy, Bastuji et al., Prog. Neuro-Psych. Biol. Psych., 1988, 12, 695.
Modafinil has also been described as an agent with activity in the central nervous system. U.S. Pat. No. 5,180,745 discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the treatment of Parkinson's disease. The levorotatory form of modafinil, i.e., (−) or R-benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression, hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855). EP-A-547952 discloses the use of modafinil as an anti-ischemic agent. EP-A-594507 discloses the use of modafinil to treat urinary incontinence. In addition, modafinil may be useful in the treatment of eating disorders, or to promote weight gain or stimulate appetite in human or animals (U.S. Ser. No. 09/640,824, incorporate herein by reference) or in the treatment of attention deficit disorders (ADHD), or fatigue, especially fatigue associated with multiple sclerosis (U.S. Pat. No. 6,346,548 incorporated herein by reference).
Preparations of modafinil having a defined solid particle size are described in US RE 37516 and preparations of a levorotatory isomer of modafinil are described in U.S. Pat. No. 4,927,855, RE 37516 and U.S. Pat. No. 4,927,855 being incorporated herein by reference. Heterocyclic derivatives of modafinil are disclosed in the application U.S. 60/204,789.
Modafinil was launched in 1994 as Modiodal® for the treatment of idiopathic hypersomnia and narcolepsy in France. In the United States, it was launched as Provigil® for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy (1999) and more recently has been approved for EDS associated with obstructive sleep apnoea/hypopnoea syndrome and moderate-to-severe chronic shift work sleep disorder (SWSD). Modafinil is marketed as fairly large tablets containing 100 mg or 200 mg of the drug per tablet and several excipients such as a diluent, a disintegrant, a binder and a lubricant.
Solid dosage forms such as tablets or capsules and improved manufacturing processes have recently been disclosed in WO 2004/024133. Novel compressed tablets containing 100 mg to 200 mg modafinil in a 250 or 500 mg tablets or up to 90% modafinil in 225 mg tablets exhibit similar specifications as the marketed ones regarding, in particular, size and shape.
Higher unit doses may be used to simplify the dose schedule to one daily administration with the same therapeutic efficacy.
WO 2004/024134 discloses modafinil tablets of reduced overall unit size with an increase in weight percent of modafinil and a reduced weight percent of other ingredients for treating ADHD, a chronic neuropsychiatric disorder in children or adults patients, administered at a single dose of about 250 to 450 mg of modafinil per tablet within a 24-hour period.
Nevertheless, although these modafinil tablets offer potential advantages regarding dose schedule by reducing the total number of doses of modafinil required per day by a patient, and a decreased size/volume, patients may remain noncompliant to their treatment, particularly when high dosage units are indicated for the treatment of disease or disorders.
This applies in particular to patients experiencing difficulties in swallowing, or being unable to swallow tablets, or disliking swallowing tablets, or who may require a liquid to assist swallowing of tablets, such as for example pediatric or geriatric patients.
Administered via the oral route, significant plasma concentrations of modafinil have to be maintained in a therapeutic range for a sufficient period of time to continue to promote wakefulness in patients suffering of EDS associated for example with narcolepsy. Due to the short half-life of the compound, multiple dosing or high dosage forms may be necessary to maintain the patient in a wakeful state.
Thus, there is further a need for such improved oral delivery of modafinil which maintains blood concentrations at a suitable level and provides minimal variation in blood levels, to achieve a longer duration of action.
Liquid oral dosage forms of modafinil comprising a complex of a modafinil compound and a cyclodextrin are disclosed in the patent application WO 02/056915. The cyclodextrin increases bioavailability of the modafinil compound by enhancing the solubility of the modafinil compound in water.
However, dosing of active ingredients in liquid form is a random process even when using a dose spoon. Also, liquid dosage forms generally contain saccharose or sodium which are not suitable for patients subjected to a restrictive diet.
Oral lyophilizates, also called oral Lyoc™ are porous, crumbly solid preparations for oral administration disclosed for example in U.S. Pat. No. 3,767,807. They are prepared by lyophilization of an aqueous solution, of a suspension or of an emulsion of an active ingredient and excipients. Oral lyophilizates prepared from emulsions or suspensions of active ingredients are not subjected to compression and the integrity of a substance, particularly the initial particle-size distribution, may thus be preserved.
Lyophilizate manufacturing process proceeds by freezing an appropriate form of the active ingredients at very low temperature (generally at −20° C. to −50° C.). Subsequent lyophilization under reduced pressure has the advantage of protecting the active ingredients from degradation due to heat and water and to improve storage stability. As a result, oral lyophilizates exhibit an extremely low level of degradation impurities as well as an enhanced chemical and physical stability. The use of additives and preserving agents is thus generally unnecessary.
Lyophilization further increases the hydrophilic character of the particles. The porous structure of lyophilizates reduces particle agglomeration in water. Hence, the integrity of the original particle size is preserved and electrostatic phenomena are eliminated. Thus, the amount of excipients such as disintegrants in the formulation may be reduced.
This dosage form further affords many therapeutic advantages such as a better digestive tolerance, and a fast onset of action. Oral lyophilizate are also easily administered. They may be ingested without water by placing the Lyoc™ under the tongue, crunching between the teeth or allowing it to disintegrate in the mouth facilitating compliance as well as ambulatory treatment.
Lyophilized microbeads of modafinil are disclosed in U.S. Pat. No. 5,843,347. These beads have a diameter of about 1 mm and are prepared with modafinil particles of 2-5 μm in diameter. Hydroxypropyl- -cyclodextrin is included as an inert diluent and to improve the cohesion of the microbeads.
Due to their small size (diameter 1 mm), the microbeads are intended to be swallowed immediately without prior crunching or disintegration in the mouth, rendering the taste-masking of the modafinil bitter taste not an issue for such composition.
In addition, due to the small size of the microbeads, their modafinil dosage strength is very limited. This dosage form is thus not suitable for a convenient administration of high strength modafinil dosages.
There is thus a need for an oral dosage form of modafinil, in particular aimed to deliver high dosage forms, which is easy to swallow and has an acceptable taste. It is further desirable to provide such a dosage form which further allows controlled release.